Active ingredients: Ertapenem
INVANZ 1 g powder for concentrate for solution for infusion
Why is Invanz used? What is it for?
INVANZ contains ertapenem which is an antibiotic belonging to the beta-lactam group. It is effective against a broad spectrum of bacteria (microbes) that cause infections in various parts of the body.
INVANZ can be given to individuals from 3 months of age.
Treatment:
Your doctor has prescribed INVANZ for you or your child to treat one (or more) of the following types of infections:
- Abdominal infections
- Lung infection (pneumonia)
- Gynecological infections
- Foot Skin Infections in Diabetic Patients.
Prevention:
- Prevention of surgical site infection in adults after colon or rectal surgery.
Contraindications When Invanz should not be used
Do not use INVANZ
- if you are allergic to the active substance (ertapenem) or any of the other ingredients of this medicine (listed in section 6)
- if you are allergic to antibiotics such as penicillins, cephalosporins or carbapenems (which are used to treat infections of various kinds).
Precautions for use What you need to know before you take Invanz
Talk to your doctor, pharmacist or nurse before taking INVANZ.
During treatment, if you have an allergic reaction (such as swelling of the face, tongue or throat, difficulty breathing or swallowing, skin rash), tell your doctor immediately as you may need urgent medical treatment.
While antibiotics, including INVANZ, are effective against some bacteria, other bacteria and fungi can continue to grow longer than normal. This phenomenon is called overgrowth. Your doctor will monitor you to check for overgrowth and to treat you if necessary.
It is important that you tell your doctor if you have diarrhea before, during or after treatment with INVANZ. This is because he may have a condition known as colitis (an "inflammation of the intestine"). Do not take any type of medicine to treat diarrhea without first checking with your doctor.
Tell your doctor if you are taking medicines containing valproic acid or sodium valproate (see Other medicines and INVANZ below).
Tell your doctor about any medical problems you currently have or have had in the past, including:
- Kidney disease. It is very important for your doctor to know if you have kidney disease and if you are undergoing dialysis treatment
- Allergies to any medicines, including antibiotics
- Disorders of the central nervous system, such as localized tremors, or seizures.
Children and adolescents (aged 3 months to 17 years)
Experience with INVANZ is limited in children less than two years of age. In this age group, the physician must decide on the potential benefit of using the drug. There is no experience with children under 3 months of age.
Interactions Which drugs or foods can change the effect of Invanz
Tell your doctor if you are taking or might take any other medicines, including those that you can buy without a prescription.
Tell your doctor, nurse or pharmacist if you are taking medicines containing valproic acid or sodium valproate (used to treat epilepsy, bipolar disorder, migraine or schizophrenia). This is because INVANZ can affect how some other medicines work. Your doctor will decide. if you need to use INVANZ in combination with these other medicines.
Warnings It is important to know that:
Pregnancy and breastfeeding
It is important to tell your doctor if you are pregnant or planning to become pregnant before starting therapy with INVANZ. INVANZ has not been studied in pregnant women. INVANZ should not be used in pregnancy unless your doctor decides that the potential benefits justify the possible risk to the fetus.
It is important to tell your doctor if you are breast-feeding or planning to breast-feed before starting therapy with INVANZ. Women taking INVANZ should not breastfeed because the drug has been found in breast milk and as a result the infant may be affected.
Driving and using machines
Do not drive or operate machinery until you know how you react to the medicine.
Some undesirable effects, such as dizziness and somnolence, have been reported with the use of INVANZ; in some patients these effects may affect the ability to drive or use machines.
INVANZ contains sodium
This medicinal product contains approximately 6.0 mEq (approximately 137 mg) sodium per 1.0 g dose and this should be taken into consideration by patients on low sodium diets.
Dose, Method and Time of Administration How to use Invanz: Posology
INVANZ must always be prepared and administered intravenously (into a vein) by a doctor or other healthcare professional. The recommended dose of INVANZ for adults and adolescents from 13 years of age is 1 gram (g) once a day.
The recommended dose for children aged 3 months to 12 years is 15 mg / kg administered twice a day (not to exceed 1 g per day). The doctor will decide on the necessary duration of treatment.
The recommended dose of INVANZ for the prevention of surgical site infections after colon or rectal surgery is 1 g administered as a single intravenous dose 1 hour before the surgical incision.
It is very important that you continue to take INVANZ for as long as your doctor prescribes it.
If you forget to take INVANZ
If you think you have forgotten a dose, contact your doctor or healthcare professional immediately.
Overdose What to do if you have taken too much Invanz
If you think you have taken too much INVANZ, contact your doctor or healthcare professional immediately.
Side Effects What are the side effects of Invanz
Like all medicines, this medicine can cause side effects, although not everybody gets them.
Adults aged 18 and over:
Serious allergic reactions (anaphylaxis), hypersensitivity syndromes (allergic reactions including rash, fever, abnormal blood tests) have been reported since the marketing of the medicine. The first signs of a serious allergic reaction may include swelling of the face and / or throat.If these symptoms occur, tell your doctor immediately as you may need urgent medical treatment.
The most common side effects (more than 1 in 100 patients and less than 1 in 10 patients) are:
- Headache
- Diarrhea, nausea, vomiting
- Skin rash, itching
- Problems with the vein where the drug was injected (including inflammation, swelling, swelling at the injection site, or extravasation of fluid into the tissues and skin around the injection area)
- Increased platelet count
- Changes in liver function tests
Less common side effects (more than 1 in 1,000 patients and less than 1 in 100 patients) are:
- Dizziness, somnolence, insomnia, mental confusion, convulsions
- Low blood pressure, slow heart rate
- Wheezing, sore throat? Constipation, fungal infection of the mouth, antibiotic-induced diarrhea, acid regurgitation, dry mouth, digestive difficulties, loss of appetite? Redness of the skin? Vaginal discharge and irritation? Abdominal pain, fatigue, fungal infection, fever, edema / swelling, chest pain, altered taste? Change in some laboratory tests of blood and urine
Rarely reported side effects (more than 1 in 10,000 patients and less than 1 in 1,000 patients) are:
- Decrease in white blood cells, decrease in platelets
- Low blood sugar levels
- Agitation, anxiety, depression, tremor
- Irregular heartbeat, increased blood pressure, bleeding, fast heartbeat
- Nasal congestion, cough, nosebleed, pneumonia, disturbed breathing sounds, wheezing
- Inflammation of the gallbladder, difficulty swallowing, fecal incontinence, yellowing of the skin and mucous membranes, liver disorders
- Inflammation of the skin, fungal infection of the skin, peeling of the skin, infection of surgical wounds
- Muscle cramps, shoulder pain
- Urinary tract infections, renal dysfunction
- Abortion, genital bleeding
- Allergy, malaise, pelvic peritonitis, changes in the white part of the eye, fainting.
The side effects reported (frequency not known) since the placing on the market of the medicine are:
- Hallucinations
- Reduction of consciousness
- Altered mental status (including aggression, delirium, disorientation, mental status changes)
- Abnormal movements
- Muscle weakness
- Uncertain walk
- Teeth coloring
Changes in blood tests have also been reported.
Children and adolescents (3 months to 17 years):
The most common side effects (more than 1 in 100 patients and less than 1 in 10 patients) are:
- Diarrhea
- Diaper rash
- Pain in the infusion area
- Changes in the number of white blood cells
- Changes in liver function tests
Less common side effects (more than 1 in 1,000 patients and less than 1 in 100 patients) are:
- Headache
- Hot flashes, high blood pressure, flat pinhead patches under the skin, red or purplish red
- Stool discolouration, black stools
- Redness of the skin, rash
- Burning, itching, redness and warmth in the infusion area, redness at the injection site
- Increased platelet count on blood test
- Changes in some laboratory blood tests
The side effects reported (frequency not known) since the placing on the market of the medicine are:
- Hallucinations
- Altered mental status (including aggression)
Reporting of side effects
If you get any side effects, talk to your doctor, nurse or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. unwanted, you can help provide more information on the safety of this medicine.
Expiry and Retention
Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the container.
The first 2 numbers indicate the month, the remaining 4 numbers indicate the year.
Do not store above 25 ° C.
Other information
What INVANZ contains
The active substance of INVANZ is ertapenem 1 g. The other ingredients are: sodium bicarbonate (E500) and sodium hydroxide (E524).
Description of what INVANZ looks like and contents of the pack
INVANZ is a white to off-white lyophilized powder for concentrate for solution for infusion.
INVANZ solutions range from colorless to pale yellow. Color variations within this spectrum do not alter the potency of the drug.
INVANZ is supplied in packs of 1 vial or 10 vials.
Not all pack sizes may be marketed.
The following information is intended for medical and healthcare professionals only
Instructions for reconstituting and diluting INVANZ:
To be used only once.
Preparation for intravenous administration:
INVANZ must be reconstituted and subsequently diluted prior to administration.
Adults and adolescents (13 to 17 years old)
- Reconstitution
Reconstitute the contents of a 1 g vial of INVANZ with 10 mL of water for injections or sodium chloride 9 mg / mL (0.9%) solution until a reconstituted solution of approximately 100 mg / mL is obtained. Shake well to dissolve.
- Dilution
For a 50 mL bag of diluent: For a 1 g dose, immediately transfer the contents of the reconstituted vial into a 50 mL bag of 9 mg / mL (0.9%) sodium chloride solution;
or,
For a 50 mL vial of diluent: For a 1 g dose, withdraw 10 mL from a 50 mL vial of sodium chloride 9 mg / mL (0.9%) solution and discard. Transfer the contents of the reconstituted 1 g INVANZ vial to the 50 mL vial of sodium chloride 9 mg / mL (0.9%) solution.
- Infusion
Proceed with the infusion for a period of 30 minutes.
Children (from 3 months to 12 years)
- Reconstitution
Reconstitute the contents of a 1 g vial of INVANZ with 10 mL of water for injections or sodium chloride 9 mg / mL (0.9%) solution until a reconstituted solution of approximately 100 mg / mL is obtained. Shake well to dissolve.
- Dilution
For a bag of diluent: transfer a volume of 15 mg / kg body weight (not to exceed 1 g / day) into a bag with sodium chloride 9 mg / mL (0.9%) solution for a final concentration of 20 mg / mL or less;
or,
For a vial of diluent: transfer a volume of 15 mg / kg body weight (not to exceed 1 g / day) into a bag with sodium chloride 9 mg / mL (0.9%) solution for a final concentration of 20 mg / mL or less.
- Infusion
Infuse in 30 minutes.
The reconstituted solution must be diluted in sodium chloride 9 mg / mL (0.9%) solution immediately after preparation. Diluted solutions should be used immediately. If not used immediately, in-use storage times are the responsibility of the operator. The diluted solutions (approximately 20 mg ertapenem / mL) are physico-chemical stable for 6 hours at room temperature (25 ° C) or for 24 hours between 2 ° C and 8 ° C (in the refrigerator). The solutions should be used within 4 hours after being removed from the refrigerator. Do not freeze the reconstituted solutions.
The reconstituted solutions should be visually inspected prior to administration for the presence of particles or discolouration where the nature of the container makes this possible. INVANZ solutions range from colorless to pale yellow. The color variations contained within these limits do not alter the power.
Unused medicine and waste derived from this medicine must be disposed of in accordance with local regulations.
Expiry "> Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
INVANZ 1 G POWDER FOR CONCENTRATE FOR SOLUTION FOR INFUSION
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each vial contains 1.0 g of ertapenem.
Excipient with known effects
Each 1.0 g dose contains approximately 6.0 mEq of sodium (approximately 137 mg).
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Powder for concentrate for solution for infusion. White to off-white powder.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Treatment
INVANZ is indicated in pediatric patients (aged 3 months to 17 years) and adults for the treatment of the following infections when they are caused by bacteria with known or very likely susceptibility to ertapenem and when parenteral therapy is required (see sections 4.4 and 5.1):
• Intra-abdominal infections
• Community-acquired pneumonia
• Acute gynecological infections
• Skin and soft tissue infections of the diabetic foot (see section 4.4)
Prevention
INVANZ is indicated in adults for prophylaxis of surgical site infection following elective colorectal surgery (see section 4.4).
Refer to official guidelines on the appropriate use of antibacterial agents.
04.2 Posology and method of administration
Dosage
Treatment
Adults and adolescents (aged 13-17 years): The dose of INVANZ is 1 gram (g) administered once daily intravenously (see section 6.6).
Infants and children (aged 3 months to 12 years): The dose of INVANZ is 15 mg / kg twice daily (not to exceed 1 g / day) intravenously (see section 6.6).
Prevention
Adults: The recommended dose for the prevention of surgical site infections following elective colorectal surgery is 1 g administered as a single intravenous dose which must be completed within 1 hour prior to surgical incision.
Pediatric population
The safety and efficacy of INVANZ in children aged less than 3 months have not yet been established. No data are available.
Renal impairment
INVANZ can be used for the treatment of infections in adult patients with mild to moderate renal impairment. No dose adjustment is required for patients with creatinine clearance> 30 mL / min / 1.73 m2. The available data on the safety and efficacy of ertapenem in patients with severe renal impairment do not allow to establish a recommended dose. Ertapenem should therefore not be used in these patients (see section 5.2). There are no data in children and adolescents with renal impairment.
Hemodialysis
The available data on the safety and efficacy of ertapenem in hemodialysis patients do not allow to establish a recommended dose. Ertapenem should therefore not be used in these patients.
Hepatic impairment
No dose adjustment is recommended in patients with impaired hepatic function (see section 5.2).
Senior citizens
The recommended dose of INVANZ should be administered, except in cases of severe renal impairment (see section Renal impairment).
Method of administration
Intravenous administration: the INVANZ infusion should be performed over a 30 minute period.
INVANZ therapy normally lasts from 3 to 14 days, but may vary depending on the type and severity of the infection and the causative pathogen (s). When clinically indicated, it can be passed to an adequate oral antibacterial agent, if clinical improvement is observed.
For instructions on preparation of the medicinal product before administration, see section 6.6.
04.3 Contraindications
• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1
• Known hypersensitivity to any other carbapenem antibacterial agent
• Severe hypersensitivity (eg, anaphylactic reaction, severe skin reaction) to any other type of beta-lactam antibacterial agent (eg, penicillins or cephalosporins).
04.4 Special warnings and appropriate precautions for use
Hypersensitivity
Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving beta-lactams. Such reactions are more likely in individuals with a history of sensitivity to multiple allergens. A careful medical history should be taken prior to initiation of therapy with ertapenem to ascertain the presence of previous hypersensitivity reactions to penicillins, cephalosporins, other beta-lactams and other allergens (see section 4.3). If an allergic reaction to ertapenem occurs (see section 4.8), discontinue therapy immediately Serious anaphylactic reactions require urgent treatment.
Superinfection
Prolonged use of ertapenem may result in the proliferation of non-susceptible organisms. Repeated evaluation of the patient's condition is essential. If superinfection occurs during therapy, appropriate measures should be taken.
Antibiotic associated colitis
Episodes of antibiotic-associated colitis and pseudomembranous colitis have been reported with ertapenem, ranging from mild intensity to life-threatening intensity. Therefore, it is important to consider this diagnosis in patients who present with diarrhea following the administration of antibacterial agents. Consideration should be given to discontinuing INVANZ therapy and establishing specific treatment for Clostridium difficile. Medicinal products that inhibit peristalsis should not be given.
Convulsions
Seizures have been reported in adult patients during therapy with ertapenem (1 g once daily) or during the 14-day follow-up period in clinical trials. Seizures occurred most commonly in elderly patients and in patients with a history of central nervous system (CNS) disorders (e.g. brain injury or history of seizures) and / or impaired renal function. Similar observations were made in post-marketing conditions.
Concomitant use with valproic acid
The concomitant use of ertapenem and valproic acid / sodium valproate is not recommended (see section 4.5).
Optimal sub exposure
Based on the available data, it cannot be excluded that in the few cases of surgery lasting more than 4 hours patients may be exposed to suboptimal concentrations of ertapenem and consequently to a risk of potential therapeutic failure. In these unusual cases, caution should therefore be exercised.
Excipient
This drug contains approximately 6.0 mEq (approximately 137 mg) of sodium per 1.0 g dose, and this should be taken into consideration by patients on a restricted sodium diet.
Considerations for use in special populations
Experience with the use of ertapenem in the treatment of severe infections is limited. In clinical trials for the treatment of community-acquired pneumonia, in adults, 25% of evaluable patients treated with ertapenem had severe disease (defined as a pneumonia severity index> III) In a clinical study for the treatment of acute gynecological infections, in adults, 26% of evaluable patients treated with ertapenem had severe disease (defined as a temperature ≥ 39 ° C and / or bacteraemia); ten patients had bacteraemia. Among evaluable patients treated with ertapenem in a clinical study for the treatment of intra-abdominal infections, in adults, 30% had generalized peritonitis and 39% had infections from sites other than the appendix including stomach, duodenum, small intestine, colon and gallbladder; the number of evaluable patients enrolled with APACHE II scores ≥ 15 was limited and efficacy in these patients has not been established.
The efficacy of INVANZ in the treatment of community-acquired pneumonia due to Streptococcus pneumoniae penicillin-resistant has not been established.
The efficacy of ertapenem in the treatment of diabetic foot infections with concomitant osteomyelitis has not been established.
Experience with ertapenem in children under the age of two is relatively limited. In this age group, particular attention should be paid to assessing the susceptibility of the organism (s) responsible for the infection to ertapenem. There are no data in children under 3 months.
04.5 Interactions with other medicinal products and other forms of interaction
Interactions due to inhibition of P-glycoprotein-mediated clearance or CYP-mediated clearance of medicinal products are unlikely to occur (see section 5.2).
Decreases in serum valproic acid which may fall below the therapeutic range have been reported when valproic acid was co-administered with carbapenem agents. Reduced serum valproic acid levels may lead to inadequate control of seizures; therefore "Concomitant use of ertapenem and valproic acid / sodium valproate is not recommended and alternative antibacterial or anticonvulsant therapies should be considered.
04.6 Pregnancy and breastfeeding
Pregnancy
There have been no adequate and well-controlled studies in pregnant women. Animal studies do not indicate direct or indirect harmful effects on pregnancy, embryo-fetal development, parturition or postnatal development. However, Ertapenem should not be used in pregnancy unless the potential benefit outweighs the possible risk to the fetus.
Feeding time
Ertapenem is excreted in breast milk. Due to the potential adverse reactions in the infant, mothers should not breastfeed during therapy with ertapenem.
Fertility
There are no adequate and well-controlled studies regarding the effect of ertapenem use on fertility in men and women. Preclinical studies do not indicate direct or indirect harmful effects on fertility (see section 5.3).
04.7 Effects on ability to drive and use machines
No studies on the ability to drive and use machines have been performed.
INVANZ may affect patients' ability to drive or use machines. Patients should be informed that dizziness and somnolence have been reported with the use of INVANZ (see section 4.8).
04.8 Undesirable effects
Summary of the safety profile
Adults
The total number of patients treated with ertapenem in clinical trials was over 2,200, of which more than 2,150 received a 1 g dose of ertapenem. Adverse reactions (reactions considered by the investigator to be possibly, probably or certainly related to the use of the medicine) have been reported in approximately 20% of patients treated with ertapenem. Therapy was suspended due to adverse reactions deemed related to the drug in the " 1.3% of patients. In a clinical study for the prophylaxis of surgical site infections after colorectal surgery, an additional group of 476 patients were treated with a single 1 g dose of ertapenem before undergoing surgery.
For patients who received only INVANZ, the most common adverse reactions reported during therapy or during the 14-day follow-up following discontinuation of treatment were: diarrhea (4.8%), complications of the perfused vein (4.5%) and nausea (2.8%).
For patients administered INVANZ alone, the most frequently reported deviations from normal laboratory values and their respective incidence rates during therapy and follow-up for 14 days after stopping treatment were: ALT (4.6%), AST (4.6%), alkaline phosphatase (3.8%) and platelet count (3.0%).
Pediatric population (aged 3 months to 17 years):
The total number of patients treated with ertapenem in clinical studies was 384. The overall safety profile is comparable to that of adult patients. Adverse reactions (i.e., considered by the investigator to be possibly, probably or certainly drug related) were reported in approximately 20.8% of patients treated with ertapenem.Treatment was discontinued due to adverse reactions in 0.5% of patients.
For patients who received only INVANZ, the most common adverse reactions reported during therapy and follow-up for 14 days after stopping treatment were: diarrhea (5.2%) and pain at the site of infusion (6.1%).
For patients administered INVANZ alone, the most frequently reported deviations from normal laboratory values and their respective incidence rates during therapy and follow-up for 14 days after stopping treatment were: decreases in neutrophil count (3.0%) and ALT (2.9%) and AST (2.8%) elevations.
Table of adverse reactions
For patients who received only INVANZ, the following adverse reactions were reported during therapy or during the 14 follow-up days after treatment discontinuation: Common (≥ 1/100,
Reporting of suspected adverse reactions
Reporting of suspected adverse reactions occurring after authorization of the medicinal product is important as it allows continuous monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system. in "Annex V.
04.9 Overdose
No specific information is available on the treatment of overdose with ertapenem. Cases of overdose with ertapenem are unlikely to occur. Intravenous administration of 3 g of ertapenem daily for 8 days to healthy adult volunteers caused no major toxicity episodes. In clinical trials in adults, accidental administration of doses up to 3 g in one day did not cause clinically relevant adverse reactions. In pediatric clinical trials, a single intravenous (IV) dose of 40 mg / kg up to a maximum of 2 g resulted in no toxicity.
In the event of overdose, however, treatment with INVANZ should be discontinued and general therapeutic support measures instituted until renal elimination of the drug.
Ertapenem can be partially eliminated by hemodialysis (see section 5.2); however, no information is available on the use of hemodialysis in the treatment of overdose.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: antibacterials for systemic use, carbapenems.
ATC code: J01DH03.
Mechanism of action
Ertapenem inhibits bacterial wall synthesis following adhesion to penicillin-binding proteins (PBPs). Escherichia coli, the strongest affinity is towards PBPs 2 and 3.
Pharmacokinetic / Pharmacodynamic (PK / PD) relationship
In line with other beta-lactam antimicrobial agents, the parameter that provides the best correlation with efficacy in preclinical PK / PD studies has been shown to be the number of times the MIC of ertapenem is higher than that of the infecting organism. .
Resistance mechanism
For species considered susceptible to ertapenem, resistance was uncommon in surveillance studies conducted in Europe. In resistant isolates, resistance to other antibacterial agents of the carbapenem class was observed in some but not all isolates. Ertapenem is fully stable to hydrolysis by most classes of beta-lactamases, including penicillinases, cephalosporinases and extended spectrum beta-lactamases, but not metallo-beta-lactamases.
Methicillin-resistant staphylococci and enterococci are resistant to ertapenem due to non-sensitivity to the PBP target; P. aeruginosa and other non-fermenting bacteria are generally resistant, probably due to limited penetration and active efflux.
Resistance in Enterobacteriaciae is uncommon and ertapenem is generally active against those with extended spectrum beta-lactamase (ESBL). However, resistance may be observed when ESBLs or other potent beta-lactamases (e.g. AmpC types) are present together with a reduction in permeability, resulting from the loss of one or more external membrane porins, or with upregulation of efflux. Resistance may also emerge through the acquisition of beta-lactamases with significant hydrolyzing activity of carpapenems (eg IMP and VIM metallo-beta-lactamases or KPC types), although the latter are rare.
The mechanism of action of ertapenem differs from that of other classes of antibiotics such as quinolones, aminoglycosides, macrolides and tetracyclines. There is no target-based cross-resistance between ertapenem and these substances. However, microorganisms may show resistance to more than a class of antibacterial agents when the mechanism is, or includes, impermeability to certain compounds and / or an efflux pump.
Breakpoint
The EUCAST MIC breakpoints are as follows:
• Enterobacteriacea: ≤ 0.5 mg / L and R> 1 mg / L
• Streptococcus A, B, C, G: S ≤ 0.5 mg / L and R> 0.5 mg / L
• Streptococcus pneumoniae: S ≤ 0.5 mg / L and R> 0.5 mg / L
• Haemophilus influenzae: S ≤ 0.5 mg / L and R> 0.5 mg / L
• M. catarrhalis: S ≤ 0.5 mg / L and R> 0.5 mg / L
• Gram negative anaerobes: S ≤ 1 mg / L and R> 1 mg / L
• Species not related to breakpoints: S ≤ 0.5 mg / L and R> 1 mg / L
(NB: The sensitivity of staphylococci to ertapenem is inferred from the sensitivity to methicillin)
Physicians are advised that local MIC breakpoints, if available, should be consulted.
Microbiological sensitivity
The prevalence of acquired resistance may vary geographically and over time for selected species and local information on resistance is desirable, particularly when treating severe infections. Localized clusters of infection with carbapenem-resistant organisms have been reported in the European Union. The information below provides only rough guidance on whether or not a microorganism is susceptible to ertapenem.
* Activity has been satisfactorily demonstrated in clinical trials.
† The efficacy of INVANZ in the treatment of community-acquired pneumonia from Streptococcus pneumoniae penicillin-resistant has not been established.
+ frequency of acquired resistance> 50% in some member states
# Methicillin-resistant staphylococci (including MRSA) are always resistant to beta-lactams.
Information from clinical studies
Efficacy in pediatric studies
Ertapenem has been evaluated primarily for pediatric safety and secondly for efficacy in randomized multicenter comparative studies in pediatric patients aged 3 months to 17 years.
The proportion of patients with favorable clinical response to post-treatment visit in the MITT population is shown in the table below:
05.2 Pharmacokinetic properties
Plasma concentrations
Mean plasma concentrations of ertapenem following a single 30 minute intravenous infusion of a 1 g dose in healthy young adults (25 to 45 years of age) were 155 mcg / mL (Cmax) at 0.5 hours. postdose (at the end of the infusion), 9 mcg / mL at 12 hours postdose and 1 microgram / mL at 24 hours postdose.
The area under the plasma concentration curve (AUC) for ertapenem in adults increases in an almost dose-proportional manner over dose values between 0.5 and 2 g.
There is no accumulation of ertapenem in adults following multiple intravenous infusions of doses ranging from 0.5 to 2 g per day.
The mean plasma concentrations of ertapenem following a single 30 minute intravenous infusion of a dose of 15 mg / kg (up to a maximum dose of 1 g) in patients aged 3 to 23 months were 103.8 μg / mL (Cmax) at 0.5 hours after dose administration (end of infusion), 13.5 mcg / mL at 6 hours after dose administration, and 2.5 mcg / mL at 12 hours after dose administration dose.
The mean plasma concentrations of ertapenem following a single 30 minute intravenous infusion of a dose of 15 mg / kg (up to a maximum dose of 1 g) in patients aged 2 to 12 years were 113.2 micrograms / mL (Cmax) at 0.5 hours after dosing (end of infusion), 12.8 mcg / mL at 6 hours after dosing, and 3.0 mcg / mL at 12 hours after dosing dose.
The mean plasma concentrations of ertapenem following a single 30 minute intravenous infusion of a dose of 20 mg / kg (up to a maximum dose of 1 g) in patients aged 13-17 years were 170.4 micrograms / mL (Cmax) at 0.5 hours after dose administration (end of infusion), 7.0 mcg / mL at 12 hours after dose administration, and 1.1 mcg / mL at 24 hours after dose administration dose.
The mean plasma concentrations of ertapenem following a 30-minute intravenous infusion of a single dose of 1 g in three patients aged 13-17 years were 155.9 μg / mL (Cmax) at 0.5 hours later. administration of the dose (end of infusion), and 6.2 mcg / mL at 12 hours after administration of the dose.
Distribution
Ertapenem is extensively bound to human plasma proteins. In healthy young adults (25 to 45 years of age), protein binding of ertapenem decreases as plasma concentrations increase from approximately 95% bound drug to an indicative plasma concentration.
The volume of distribution (Vdss) of ertapenem in adults is approximately 8 liters (0.11 liters / kg) and approximately 0.2 liters / kg in pediatric patients aged 3 months to 12 years and approximately 0, 16 liters / kg in pediatric patients aged 13-17 years.
The ertapenem concentrations achieved in adult skin vesicle fluid for each collection on the third day of treatment with an intravenous dose of 1 g per day showed a ratio of vesicle fluid AUC to plasma AUC of 0.61.
Education in-vitro indicate that the effect of ertapenem on plasma protein binding of high affinity binding medicinal products (warfarin, ethinylestradiol and norethindrone) was small. The change in the protein bound fraction was In-vivo, probenecid (500 mg every 6 hours) decreased the plasma fraction of ertapenem linked at the end of the infusion in people treated with a single intravenous dose of 1 g from approximately 91% to approximately 87%. The effects of this change are expected to be transient A clinically significant interaction due to the displacement of another medicinal product by ertapenem or vice versa is unlikely.
Education in-vitro indicate that ertapenem does not inhibit P-glycoprotein-mediated transport of digoxin or vinblastine and that ertapenem is not a substrate for P-glycoprotein-mediated transport.
Biotransformation
In healthy young adults (23 to 49 years of age), after intravenous infusion of 1 g radiolabelled ertapenem, plasma radioactivity consists predominantly (94%) of ertapenem. The major metabolite of ertapenem is the open-loop derivative formed by dihydropeptidase-I mediated beta-lactam ring hydrolysis.
Education in-vitro on human liver microsomes indicate that ertapenem does not inhibit metabolism mediated by the six major CYP isoforms: 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4.
Elimination
Following intravenous administration of a 1 g dose of radiolabelled ertapenem to healthy young adults (23 to 49 years of age), approximately 80% of the drug is recovered in the urine and 10% in the faeces.Of the 80% recovered in the urine, approximately 38% is excreted as unchanged ertapenem and approximately 37% as an open-ring metabolite.
In healthy young adults (18 to 49 years of age) and in patients 13 to 17 years of age given an intravenous dose of 1 g, the plasma half-life is approximately 4 hours. The plasma half-life is approximately 4 hours. average in children aged 3 months to 12 years is about 2.5 hours. Mean concentrations of ertapenem in urine were above 984 mcg / mL over 0 to 2 hours post dose and above 52 mcg / mL over 12 to 24 hours post dose.
Special populations
Sex
The plasma concentrations of ertapenem are comparable in men and women.
Senior citizens
Plasma concentrations of ertapenem following an intravenous dose of 1 g and 2 g are slightly higher (approximately 39% and 22%, respectively) in healthy elderly people (≥ 65 years) compared to young adults (
Pediatric population
The plasma concentrations of ertapenem following a 1 g once daily intravenous dose are comparable in pediatric patients aged 13-17 years and in adults.
After a dose of 20 mg / kg (up to a maximum dose of 1 g), the pharmacokinetic parameter values in patients aged 13-17 years were generally comparable to those found in healthy young adults. To provide an estimate of the pharmacokinetic data under the assumption that all patients in this age group were treated with a 1 g dose, the pharmacokinetic data were calculated by adjusting for a 1 g dose, assuming a " of linearity. A comparison of the results shows that a dose of 1 g of ertapenem once daily achieves a pharmacokinetic profile comparable to that of adults in patients aged 13-17 years. The ratios (13 to 17 years / adults) for AUC, concentration at the end of the infusion, and concentration at the median of the dose range were 0.99, 1.20, and 0.84, respectively.
Plasma concentrations at the median dose range following a single 15 mg / kg intravenous dose of ertapenem in patients aged 3 months to 12 years were comparable to plasma concentrations at the median dose range. after a dose of 1 g once daily intravenous administration in adults (see section Plasma concentrations). The plasma clearance (mL / min / kg) of ertapenem in patients 3 months to 12 years of age is approximately 2-fold higher than that seen in adults. At a dose of 15 mg / kg, the AUC value is The plasma concentrations at the median of the dose range in patients aged 3 months to 12 years were comparable to those seen in healthy young adults treated with a 1 g intravenous dose of ertapenem.
Hepatic impairment
The pharmacokinetics of ertapenem in patients with hepatic impairment have not been established. As the hepatic metabolism of ertapenem is limited, its pharmacokinetics are not expected to be changed in the event of impaired hepatic function. Therefore, no dose adjustment is recommended in patients with impaired hepatic function.
Renal impairment
Following a single intravenous dose of 1 g of ertapenem in adults, the AUC of ertapenem in full (bound and unbound) and unbound ertapenem are similar in patients with mild renal impairment (ClCr 60 - 90 mL / min / 1.73 m2) compared to healthy subjects (age 25 - 82 years). In comparison to healthy adult subjects, in patients with moderate renal impairment (ClCr 31 - 59 mL / min / 1.73 m2) the AUC of ertapenem in full and unbound ertapenem increased approximately 1.5 and 1.8-fold, respectively. In comparison to healthy adult subjects, in subjects with severe renal impairment (ClCr 5 - 30 mL / min / 1.73 m2) the AUC of ertapenem in full and unbound ertapenem increased approximately 2.6-fold and 3.4-fold, respectively. Compared to healthy subjects, ertapenem AUC in hemodialysis patients in full and unbound ertapenem increased approximately 2.9 and 6.0-fold, respectively, during the interval between hemodialysis sessions. After a single 1 g intravenous dose given immediately prior to a hemodialysis session, approximately 30 % of the dose is recovered in the dialysis fluid There are no data in pediatric patients with renal impairment.
The available data on the safety and efficacy of ertapenem in patients with advanced renal impairment and in hemodialysis patients do not allow to establish a recommended dose. Ertapenem should therefore not be used in these patients.
05.3 Preclinical safety data
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, reproductive and developmental toxicity. However, decreases in neutrophil counts occurred in rats given high-dose ertapenem, a phenomenon not considered relevant to safety.
Long-term studies in animals have not been performed to evaluate the carcinogenic potential of ertapenem.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Sodium bicarbonate (E500)
Sodium hydroxide (E524) to adjust the pH to 7.5
06.2 Incompatibility
Do not use solvents or infusion fluids containing dextrose to reconstitute or administer ertapenem.
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.
06.3 Period of validity
2 years.
After reconstitution:
Diluted solutions should be used immediately. If not used immediately, in-use storage times are the responsibility of the operator. The diluted solutions (approximately 20 mg ertapenem / mL) are physico-chemical stable for 6 hours at room temperature (25 ° C) or for 24 hours between 2 ° C and 8 ° C (in the refrigerator). The solutions should be used within 4 hours after being removed from the refrigerator. Do not freeze INVANZ solutions.
06.4 Special precautions for storage
Do not store above 25 ° C.
For storage conditions after reconstitution, see section 6.3.
06.5 Nature of the immediate packaging and contents of the package
15 mL Type I glass vials with a gray butyl stopper and a white plastic cap on an aluminum safety band.
Supplied in packs of 1 vial or 10 vials.
Not all pack sizes may be marketed.
06.6 Instructions for use and handling
Instructions for Use:
To be used only once.
Reconstituted solutions should be diluted in sodium chloride 9 mg / mL (0.9%) solution immediately after preparation.
Preparation for intravenous administration :
INVANZ must be reconstituted and subsequently diluted prior to administration.
Adults and adolescents (from 13 to 17 years old) Reconstitution
Reconstitute the contents of a 1 g vial of INVANZ with 10 mL of water for injections or sodium chloride 9 mg / mL (0.9%) solution until a reconstituted solution of approximately 100 mg / mL is obtained. Shake well to dissolve (see section 6.4.)
Dilution
For a 50 mL bag of diluent: For a 1 g dose, immediately transfer the contents of the reconstituted vial into a 50 mL bag of 9 mg / mL (0.9%) sodium chloride solution; or,
For a 50 mL vial of diluent: For a 1 g dose, withdraw 10 mL from a 50 mL vial of sodium chloride 9 mg / mL (0.9%) solution and discard. Transfer the contents of the reconstituted 1 g INVANZ vial to the 50 mL vial of sodium chloride 9 mg / mL (0.9%) solution.
Infusion
Proceed with the infusion for a period of 30 minutes.
Children (from 3 months to 12 years) Reconstitution
Reconstitute the contents of a 1 g vial of INVANZ with 10 mL of water for injections or sodium chloride 9 mg / mL (0.9%) solution until a reconstituted solution of approximately 100 mg / mL is obtained. Shake well to dissolve (see section 6.4.)
Dilution
For a bag of diluent: transfer a volume of 15 mg / kg body weight (not to exceed 1 g / day) into a bag with sodium chloride 9 mg / mL (0.9%) solution for a final concentration of 20 mg / mL or less; or,
For a vial of diluent: transfer a volume of 15 mg / kg body weight (not to exceed 1 g / day) into a bag with sodium chloride 9 mg / mL (0.9%) solution for a final concentration of 20 mg / mL or less.
Infusion
Infuse in 30 minutes.
Compatibility of INVANZ with intravenous solutions containing sodium heparin and potassium chloride has been demonstrated.
The reconstituted solutions should be visually inspected prior to administration for the presence of particles or discolouration where the nature of the container makes this possible. INVANZ solutions range from colorless to pale yellow. The color variations contained within these limits do not alter the power.
Unused medicine and wastes derived from this medicine must be disposed of in accordance with local regulations.
07.0 MARKETING AUTHORIZATION HOLDER
Merck Sharp & Dohme Limited Hertford Road, Hoddesdon Hertfordshire EN11 9BU
UK
08.0 MARKETING AUTHORIZATION NUMBER
EU / 1/02/216/001
035851017
EU / 1/02/216/002
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
Date of first authorization: April 18, 2002
Date of most recent renewal: December 22, 2011
10.0 DATE OF REVISION OF THE TEXT
D.CCE 11/1/2017
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